Synthesis of vitamin a esters and ethers



Patented July 8, 1958 United States Patent ce 2,842,600

results in a loss of alcohol and the formation of Compound II having the formula 2,842,600

SYNTHESIS OF VITAMIN A ESTERS AND ETHERS 5 William Oroshnik, Plainfield, N. J., and Alexander 1). CH CH Mebane, New York, N. Y., assignors to Ortho Pharmaceutical Corporation, a corporation of New Jersey H2 OH=GH JJ OH=OH OH=Z?OH=OH, No Drawing. Application June 19, 1956 H I Serial No. 592,251

11 Claims. (Cl. 260-611) I This invention relates to compositions of matter and to .15 7 methods for preparing the same and particularly relates Compound II to a process for the preparation of vitamin A ethers. and esters and to compositions of matter which are inter- Although sodamide in liquid ammonia is the preferred remediates in the process. agent for use in the conversion of Compound I to Com- The present application is a continuation-in-part of appound II, any metallic amide, such as the alkali metal plication Serial No. 343,784, filed March 20, 1953. amid-es, i. e., potassium and lithium amides, and the al- It is an object of this invention to prepare compounds kaline earth amides, i. e., calcium amide; and other solto be used in the preparation of vitamin A and its de- 5 vents such as ether, and pyridine or other nitrogenous rivatives. solvents may also be used. a

It is another object of this invention to provide a proc- Compound II, in the presence of strong or weak acids ess for the preparation of vitamin A and its derivatives. or Lewis acids of which boron trifluoride is preferred, may Other objects of this invention will be apparent from undergo the allylic rearrangement-dehydration illustrated the description f ll i and the appended claims. in Table I to give anhydrovitamin A, identical in every It has now been discovered that ethers and esters f way with that formed from vitarninAitself. Under care vitamin Amay prepared fr compound having the 1 fully controlled conditions of acidity, it is possible to following formula: isolate the intermediate Compounds III and IV shown in Table I. If the rearrangement is done in methanol, the

intermediate compound may be a tertiary methoxyl Compound III, and if the rearrangement is carried out in aqueous media, the rearrangement product may be a hy- H, H, droxyl Compound IV. These rearrangement products E i can react in either or both of two ways: (1) Compound OH=OH CH=CH OH' =CH GHTOR III can rearrange to vitamin A methyl ether in methanol,

HP OH: H or (2) it can lose the elements of methanol to form a i 2'- double bond in the ring, giving anhydrovitamin A.

H: v The intermediate compound IV can rearrange to vitamin A or vitamin A esters (in the presence of organic acids) by Reaction 1; or Compound IV can also dehydrate to anhydrovitamin A by Reaction 2. The rearrangecompound I I I ment of Compounds III and IV may be carried out to W -advantage under conditions where the acidity is not too in whichR is alower alkyl radical. The preparation and Strong- Y the use Of methanol aqueous tertiary properties of Compound I are given by William Oroshnik, 55 butanol a Solvent and the Presence of Catalytic q G, Kaunas and "Mebane, J ur al f the American titles of boron trifluoride, which acts as an acid in these Chemical Society, volume 74, page 295 (1952), i media, one can obtain vitamin A ethers or vitamin A The treatment of Compound I with a metallie'amide alcohol.

The invention will be further illustrated by the followfrom which the air had been removed by alternatingly ing examples: evacuating and flushing with nitrogen, was cooled to TABLE I OH: CH!

(IJ s a H2- CH=CHCOH=CHCH=COH=CH:

on I Methanol H OH; Compound II Tertiary 11+ 11+ butauol 1/ z \1 CH3 CH3 CH3 CH3 (3H3 (7H3 (1H3 ([1113 Ha- =CH-CH=C-CH=CHCH=O-CH=OH1 H1- =CH-CH=CCH=CH-CH=C-CH=CH:

H O CH5 Compound III Hg- OH Compound IV CH3 H1 CH3 H+/ 114- I V X14,

om 0H. 3 on. on. CH3 CH1 ona on,

I l i H CH=OHC l=OHOH=GHC H CH-OH=C CH=OHCH=O H H OH=CHC=CH-CH=CH("3 H OH: CH-CH2OM9 H CH: CH=CH2 H CH: CH-CHz-OH H7 H H:

Compound VI Compound V Compound VIII Vitamin A methyl ether Anhydro-vitamtn A Vitamin A CH; CH,

CH: CHr H CH=CH-f7=OHCH=OHl=CH-CH1OC-OH:

Compound VII Hr- CH3 Vitamin A acetate Example I 35 C. and treated with two drops of boron trifluoride PREPARATION OF COMPOUND 11 e-therate. The reaction was stopped after seconds by adding enough ammonium hydroxide (5 drops) to neutralize all of the acid. The ultraviolet absorption spectrum of Compound II was absent, but the spectrum showed peaks at 326, 342.5, and 360.5 mu, due to the presence of Compound III. The tertiary-methoxyl compound III (Table I) was isolated as follows: The methanol solvent was evaporated under vacuum and the residue dissolved in a small quantity of petroleum ether (60-100 ml.) and chromatographed on alumina. The adsorbed compound, appearing as a white-fluorescent zone, was eluted by 2% cther-pentane mixture. The :luate on concentration under vacuum (removing the A solution of sodamide in liquid ammonia was prepared by adding 9.2 grams of metallic sodium to one liter of liquid ammonia to which had been previously added 0.2-0.5 gram of hydrated ferric nitrate. After all the sodium had reacted the solution was cooled to -40 C. and a solution of 34.0 grams of Compound I in 275 milliliters of anhydrous ether was added during ten to twenty minutes. The reaction mixture turned a brilliant ultramarine blue andremained thus for the duration of the reaction period which was two hours at 30 C. The reaction was stopped by the addition of excess amm011mm ehlonde e ammotlla allowed to P last traces of volatiles at 0.001 millimeters) was a lemonrate. The remaining ether solution was removed and yellow i 054 i h h f llo ing ti distilled. The product was collected at 95 C. at 0.001 l c l d fo (1 1-1 0; C, 8394; H, 10,73;

millimeter of mercury pressure. It was arbitrarily cut 0 1() 3 F d; C, 83,73; H, 10.85; OMe, 10.99.

into two fractions in order to concentrate the demeth- 32 3425 3605 oxylated portion as much as possible. Both fractions 34 consisted essentially of Compound II. The first fraction 44200 which weighed 20.1 grams had a refractive index at 22 The infrared spectrum proved the presence of a ter- C. of 1.5462 and showed absorption in the ultraviolet minal vinyl group (strong band at 11.17 and a tertiarywith a maximum at 2740 A. The first fraction was methoxyl group (strong band at 9.3,u). The terminal found to have a methoxyl value of 1.9%. The second vinyl group was corroborated by ozoniZa-tion, which gave fraction which weighed 3.7 grams had a refractive index 51% of formaldehyde.

at 22 C. of 1.5362 and showed absorption in the ultra- 6o violet with a maximum at 2740 A. This fraction had a Example methoxyl value of 4.1%. Both fractions were purified A solution of 1.0 g. of Compound II in 50 ml. of chromatographically on n l i Column and the 80% tertiarybutanol-20% water was chilled to the freezproduct obtained had a refractive index at 23.5 C. of e Point and treated with 1 p of boron tfifluoride 1.5509 and showed absorption in the ultraviolet with a etherate- The mixture was Stirred While allowing to melt, maximum at 2750 A. and a molecular coeflicient of'exthen Stored at After an hour, the absorption tinction (e) of 31,700. The calculated values for car- Spectrum: max 362 Showed that the bon and hydrogen were 83.86% and 10.56% respectul'e consisted p p l of compound tively. Analysis showed 83.56% carbon and 10.55% Example 1V hydrogen.

. Example H A solution of 2 g. of Compound II and a. few hydrof quinone crystals in 150 ml. of benzene was refluxed BR PA I E RATION 0F INTERMEDIATE COMPOUND In a under a water separator. Twenty-five milligrams of A solution of 1.6 grams of Compound II and a. few p-toluenesulphonic .acidmonohydrate was added. Withcrystals of hydroquinone in 320 milliliters of methanol in 15 minutes, the theoretical quantity'of water had been Example V A solution of 3 grams of Compound II and a few hydro-quinone crystals in 900 cc. of methanol was chilled to -25 C. and treated with a solution of 3 drops of boron trifluoride etherate in 100 cc. of methanol. After storage for 19 hours at 5 C., the absorption spectrum showed a vitamin A methyl ether (VI), accompanied by some anhydrovitamin A (V). The acid was neutralized with 9 drops of 28% ammonium hydroxide, and the solution was evaporated under vacuum to one-twentieth its original volume, then extracted with isoheptane and the extract dried over anhydrous K CO and chromatographed on activated alumina. After elution of anhydrovitamin A with isoheptane, the column was extruded. The main yellow-fluorescing zone was extracted with methanol and the methanol extract evaporated under vacuum, yielding 1.2 g. (37%) of vitamin A methyl ether, a yellow oil, x 326 m Example VI A solution of 1.0 g. of Compound II in 50 ml. of acetonitrile was added rapidly with stirring to 100 ml. of 95% acetic acid-5% water. A transient blue color was noted, which disappeared in a few seconds. Five grams of potassium acetate were then added. The absorption spectrum of the solution showed vitamin A acetate (VII) together with a considerable quantity of anhydrovitamin A (V). These could readily be separated by chromatography on alumina.

Example VII A solution of Compound IV, prepared as described in Example III, was allowed to stand at 5 C. for 20 hours. At the end of this time, its absorption spectrum showed that it contained vitamin A (VIII) together with a considerable quantity of anhydrovitamin A (V). These could readily be separated by chromatography on alumina.

What is claimed is:

1. The method comprising treating a compound of the formula in which R is a lower alkyl radical, with a metallic amide selected from the group consisting of alkali and alkaline earth metallic amides to provide a pentaene of the formula CH3 CH and treating the pentaene, in the presence of a compound selected from the class consisting of low-molecularweight aliphatic alcohols and acids, with a dehydrating agent to provide a member of the class consisting of vitamin A, anhydrovitamin A, low-molecular-weight aliphatic ethers of vitamin A and low-molecular-weight aliphatic esters of vitamin A.

6 2. The method comprising treating a compound of the formula in which R is a lower alkyl radical, with a metallic amide selected from the group consisting of alkali and alkaline earth metallic amides to provide a pcntaene of the formula and treating the pentaene with an acid dehydrating agent to provide anhydrovitamin A.

3. A method according to claim 1 in which the dehydrating agent is boron trifluoride etherate.

4. A method comprising treating a compound of the formula CH3 CH CH3 (3H3 with a dehydrating agent at a temperature below room temperature in the presence of a compound selected from in which R is a lower alkyl radical, with a metallic amide selected from the group consisting of alkali and alkaline earth metallic amides to provide a pentaene of the formula CH3 CH3 OH: CH:

H3 C H:

and treating the pentaene with an acid dehydrating agent in the presence of methanol to provide an intermediate having the formula 7. The method comprising treating a compound of the formula in which R is a lower alkyl radical, with a metallic amide selected from the group consisting of alkali and alkaline earth metallic amides to provide a pentaene of the formula and treating the pentaene with an acid dehydrating agent in the presence of tertiary butanol to provide an intermediate having the formula 8. The method comprising treating a compound of the formula CH: CH:

with an acid dehydrating agent in the presence of methanol to provide an intermediate having the formula 9. The method comprising treating a compound of the formula with an acid. dehydrating agent in the presence of tertiary butanol to provide an intermediate having the formula 10. A compound having the formula 11. A compound having the formula CH1 CH3 Ha CH3 References Cited in the file of this patent UNITED STATES PATENTS 2,587,457 Freed Feb. 26, 1952 OTHER REFERENCES Shantz et al.: J. Amer. Chem. Soc., vol. 65, pages 901-6 (1943).

Mitchell et al.: Organic Analysis, vol. I, 1953, page 51.

UNITED STATES PATENT OFFICE CERTIFICATE @F (IQRREMBDN July 8, 1958 Patent No. 2,842,600

William Oroshnik et all,

It is hereby certified that error appears in the printed specification of the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 4, line 45, for "(60 100 mlo read (50100 ml) column 4, line '71, for "A solution of 2 g.." read A solution of 20 go Signed and sealed this 9th day of September 1958,

(SEAL) Attest: l KARL 9 AXLINE ROBERT c. WATSON 5 Commissioner of Patents Attesting Officer 

1. THE METHOD COMPRISING TREATING A COMPOUND OF THE FORMULA
 10. A COMPOUND HAVING THE FORMULA 